Scholarly article on topic 'Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage'

Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage Academic research paper on "Psychology"

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{Amygdala / "Spatial attention" / "Urbach–Wiethe disease" / Dot-probe / "Emotional processing"}

Abstract of research paper on Psychology, author of scientific article — Morteza Pishnamazi, Abbas Tafakhori, Sogol Loloee, Amirhossein Modabbernia, Vajiheh Aghamollaii, et al.

Abstract The amygdala is believed to play a major role in orienting attention towards threat-related stimuli. However, behavioral studies on amygdala-damaged patients have given inconsistent results—variously reporting decreased, persisted, and increased attention towards threat. Here we aimed to characterize the impact of developmental amygdala damage on emotion perception and the nature and time-course of spatial attentional bias towards fearful faces. We investigated SF, a 14-year-old with selective bilateral amygdala damage due to Urbach–Wiethe disease (UWD), and ten healthy controls. Participants completed a fear sensitivity questionnaire, facial expression classification task, and dot-probe task with fearful or neutral faces for spatial cueing. Three cue durations were used to assess the time-course of attentional bias. SF expressed significantly lower fear sensitivity, and showed a selective impairment in classifying fearful facial expressions. Despite this impairment in fear recognition, very brief (100 msec) fearful cues could orient SF's spatial attention. In healthy controls, the attentional bias emerged later and persisted longer. SF's attentional bias was due solely to facilitated engagement to fear, while controls showed the typical phenomenon of difficulty in disengaging from fear. Our study is the first to demonstrate the separable effects of amygdala damage on engagement and disengagement of spatial attention. The findings indicate that multiple mechanisms contribute in biasing attention towards fear, which vary in their timing and dependence on amygdala integrity. It seems that the amygdala is not essential for rapid attention to emotion, but probably has a role in assessment of biological relevance.

Academic research paper on topic "Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage"

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Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage

Morteza Pishnamazi, Abbas Tafakhori, Sogol Loloee, Amirhossein Modabbernia, Vajiheh Aghamollaii, Bahador Bahrami, Joel S. Winston


S0010-9452(16)30077-6 10.1016/j.cortex.2016.04.012

Reference: CORTEX 1729

To appear in:

Received Date: Revised Date: Accepted Date:


14 August 2015 19 January 2016 10 April 2016

Please cite this article as: Pishnamazi M, Tafakhori A, Loloee S, Modabbernia A, Aghamollaii V, Bahrami B, Winston JS, Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage, CORTEX (2016), doi: 10.1016/j.cortex.2016.04.012.

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Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage

Author list:

Morteza Pishnamazi a,b, Abbas Tafakhori a*, Sogol Loloee a, Amirhossein Modabbernia a,c, Vajiheh Aghamollaii d, Bahador Bahrami e A, Joel S Winston ef A


a Iranian Center of Neurological Research, Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.

b Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.

c Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.

d Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran.

e UCL Institute of Cognitive Neuroscience, University College London, London, United Kingdom.

f Wellcome Trust Centre for Imaging Neuroscience, University College London, London, United Kingdom.

A These authors contributed equally to this work.

* Corresponding author:

Dr Abbas Tafakhori

Department of Neurology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. P.O. Box, 1419733141 Tel.: +98 21 66948899; Fax: +98 21 66581558 Email: Abbas Tafakhori; Morteza Pishnamazi;


Amygdala; Spatial attention; Urbach-Wiethe Disease; Dot-probe; Emotional processing Word count:

Abstract: 241 words; Article body text: 4347 words (excluding abstract, acknowledgments, financial

disclosure, references, and figure legends)

Figures: 4 (four); Tables: 0 (zero); Supplementary Data: 2 (two)

1 Abstract

2 The amygdala is believed to play a major role in orienting attention towards threat-related stimuli.

3 However, behavioral studies on amygdala-damaged patients have given inconsistent results—variously

4 reporting decreased, persisted, and increased attention towards threat. Here we aimed to characterize the

5 impact of developmental amygdala damage on emotion perception and the nature and time-course of

6 spatial attentional bias towards fearful faces. We investigated SF, a 14-year-old with selective bilateral

7 amygdala damage due to Urbach-Wiethe disease, and ten healthy controls. Participants completed a fear

8 sensitivity questionnaire, facial expression classification task, and dot-probe task with fearful or neutral

9 faces for spatial cueing. Three cue durations were used to assess the time-course of attentional bias. SF

10 expressed significantly lower fear sensitivity, and showed a selective impairment in classifying fearful

11 facial expressions. Despite this impairment in fear recognition, very brief (100ms) fearful cues could

12 orient SF's spatial attention. In healthy controls, the attentional bias emerged later and persisted longer.

13 SF's attentional bias was due solely to facilitated engagement to fear, while controls showed the typical

14 phenomenon of difficulty in disengaging from fear. Our study is the first to demonstrate the separable

15 effects of amygdala damage on engagement and disengagement of spatial attention. The findings indicate

16 that multiple mechanisms contribute in biasing attention towards fear, which vary in their timing and

17 dependence on amygdala integrity. It seems that the amygdala is not essential for rapid attention to

18 emotion, but probably has a role in assessment of biological relevance.

19 1. Introduction

20 Evolutionary pressure ensures that in systems with limited perceptual capacity, stimuli that indicate

21 potential environmental dangers receive privileged access to resources (Dolan, 2002; Ohman & Mineka,

22 2001). Numerous studies show that attention is preferentially oriented towards and maintained for longer

23 by threat-related items (Yiend, 2010). Such attentional bias has been documented using a variety of

24 stimuli (e.g. facial expressions, words, scenes) (Yiend, 2010) and evidence shows that threat-related

25 stimuli affect both engagement and disengagement components of attention (Cisler, Bacon, & Williams,

26 2009; Koster, Crombez, Van Damme, Verschuere, & De Houwer, 2004; Yiend, 2010). Attentional biases

27 are observed at time-scales encompassing both automatic and strategic stages of information processing

28 (Cisler et al., 2009; Cisler & Koster, 2010; Koster, Verschuere, Crombez, & Van Damme, 2005).

29 Abnormal attention orienting to threat is a characteristic feature of anxiety disorders (Cisler & Koster,

30 2010; Salum et al., 2013; Shechner et al., 2012) and attentional bias modification has a role in anxiety

31 treatment (Hakamata et al., 2010). However, the precise neural mechanisms that underlie attentional bias

32 towards threat-related stimuli remain unclear.

33 The current literature on the neural mechanisms of attention to threat presumes a pivotal role for the

34 amygdala (Pourtois, Schettino, & Vuilleumier, 2013). It is argued that the amygdala's bidirectional

35 connections with sensory areas enhance perceptual processing of emotional stimuli (Freese & Amaral,

36 2009; LeDoux, 2007; Vuilleumier, 2005) and amygdala is therefore responsible for early ("automatic")

37 facilitated engagement of attention to threat (Cisler & Koster, 2010; Vuilleumier, 2005). Findings suggest

38 that the later strategic stages of attention to threat and the disengagement component of attentional bias

39 are controlled by higher-order cortical networks, predominantly the prefrontal attentional network (Cisler

40 & Koster, 2010; Pourtois et al., 2013). Neuroimaging studies show that the enhanced cortical activations

41 in response to fearful faces are absent in amygdala-damaged patients (Rotshtein et al., 2010; Vuilleumier,

42 Richardson, Armony, Driver, & Dolan, 2004) and support the role of amygdala in threat-related attention.

43 However the causal involvement of amygdala in biasing attention to emotion has not been confirmed

44 (Pessoa & Adolphs, 2010). The handful of behavioral experiments on amygdala-damaged patients have

45 given inconsistent results. Out of seven published studies (Anderson & Phelps, 2001; Bach, Hurlemann,

46 & Dolan, 2015; Bach, Talmi, Hurlemann, Patin, & Dolan, 2011; Piech et al., 2010, 2011; Terburg et al.,

47 2012; Tsuchiya, Moradi, Felsen, Yamazaki, & Adolphs, 2009), only two provide positive evidence for

48 impaired attention to threat after amygdala damage (Anderson & Phelps, 2001; Bach et al., 2015). In an

49 early influential study, Anderson and Phelps (2001) showed that a patient with non-selective bilateral

50 temporal lobe lesions did not exhibit facilitated attention to aversive words during the attentional blink

51 task. However, testing the same task on two patients with focal amygdala lesions failed to replicate this

52 effect (Bach et al., 2011). Two other experiments, one using attentional blink with pictures (Piech et al.,

53 2011) and the other using continuous flash suppression paradigm (Tsuchiya et al., 2009, experiment 3)

54 also report that threat-related attentional bias persists despite amygdala damage. Another piece of positive

55 evidence comes from a visual search paradigm that showed impaired attention to angry faces after

56 amygdala damage (Bach et al., 2015). However, two other studies that employed visual search with fear-

57 related targets did not find any deficit in similar patients (Piech et al., 2010; Tsuchiya et al., 2009,

58 experiment 2). Adding to the disparity within the literature, there is one report of increased attention to

59 fear in five patients with lesions relatively selective to basolateral amygdala (Terburg et al., 2012). These

60 inconsistencies warrant further investigations to explain the exact role of amygdala in triggering and

61 maintaining the attentional bias towards threat. Particularly, what is lacking is a clear characterization of

62 behavioral consequences of amygdala damage based upon the components of attentional bias and the

63 stages of information processing (Cisler & Koster, 2010; Pourtois et al., 2013).

64 In the current study, we aim to characterize emotion perception and the temporal dynamics of spatial

65 orienting towards fearful faces in an adolescent patient with selective bilateral amygdala damage due to

66 Urbach-Wiethe disease (UWD) compared to a N=10 healthy controls. UWD is a rare genetic condition

67 that causes focal symmetrical calcifications in amygdala bilaterally with sparing of other brain regions

68 (Appenzeller et al., 2006). Several previous cases of children and adolescents with bilateral amygdala

69 damage have been reported (Emsley & Paster, 1985; Ito et al., 2000; Omrani et al., 2012; Savage,

70 Crockett, & McCabe, 1988). However, very little information could be found on the cognitive

71 consequences of amygdala damage at young ages. In particular, the attentional bias to threat has been

72 solely investigated in adult amygdala-damaged patients and few neuropsychological assessments of

73 adolescent patients have mainly focused on deficits in emotion recognition and memory (Steenberg, 2014;

74 Thornton et al., 2008). Attentional bias to threat begins very early in life (Creswell et al., 2008; LoBue &

75 DeLoache, 2010) and is consistently observed across age groups (preschoolers: LoBue, 2009; preteens:

76 Waters, Lipp, & Spence, 2004; and adolescents: Wolters et al., 2012). Threat bias appears to be present in

77 early childhood as a core function that facilitates survival and adaptive social behavior (LoBue &

78 Rakison, 2013), but biases then change as a function of development (Field & Lester, 2010). With

79 increasing age, moderating factors such as trait anxiety, past experiences and environmental events seem

80 to have a larger effect on the strength and direction of attentional biases (Field & Lester, 2010; Shechner

81 et al., 2012). However, the neural mechanisms underlying attention to threat seem not to change during

82 development (Lindstrom et al., 2009).

83 We first explored the emotional experience of our patient using a fear sensitivity questionnaire and a

84 facial expression classification task. Next, to test the spatial orientation of attention, we adopted the 'dot-

85 probe' double cuing task (MacLeod, Mathews, & Tata, 1986). This task allows drawing inferences about

86 the engagement and disengagement of attention (Koster, Crombez, Verschuere, & De Houwer, 2004) and

87 can illuminate both automatic and strategic stages of attentional bias by employing short and long cue

88 exposure durations (Koster et al., 2005). In the dot-probe task, targets are presented either at the same or

89 opposite to the location of a preceding emotionally salient cue. The difference in reaction time (RT) to

90 targets located at congruent vs. incongruent location relative to the cue is interpreted as the bias of spatial

91 attention (i.e., 'vigilance' or 'avoidance'). We employed the dot-probe task with face-pair cues that could

92 both be neutral (baseline) or comprise a neutral and fearful face. We used three cue exposure durations

93 (100, 500, 1000ms) to examine the time-course of attentional bias. Assuming that the amygdala's

94 contribution in directing attention is more critical at early stages of information processing, we expected

95 to find disparate impacts of amygdala damage on attentional bias at short versus late time-points.

96 2. Materials and Methods

2.1. Participants

Patient SF (female, 14.5 years old at the time of testing) was diagnosed with UWD after investigations

99 for epilepsy showed bilateral amygdala lesions (Omrani et al., 2012) (Fig. 1). She had a 10-year history of

100 focal seizures but had been drug- and symptom-free for 8 months when tested. Psychiatric evaluation of

101 SF did not converge to any diagnosis but revealed histories of two interpersonal traumatic events, three

102 and four years ago, and a history of suicidal ideations, with a plan as recently as a month prior to the

103 study (for more details see Supplementary Material, §1). Ten female participants, matched for gender

104 (female), handedness (right handed), age (M ± SD=14.8 ± 0.2), education (8.5 years of formal schooling),

105 home language (Persian), and socioeconomic level, were recruited as control subjects. A physician

106 interviewed the control group to confirm psychiatric and neurologic health. To measure everyday fear

107 sensitivity, SF and control participants completed the Fear Survey Schedule for Children-Revised (FSSC-

108 R) (Ollendick, 1983). The Ethics Committee at the Tehran University of Medical Sciences approved all

109 procedures and informed consent was obtained from all participants.

110 2.2. Facial expression classification

111 Color face images from Radboud Face Database (RaFD) (Langner et al., 2010) were employed. A set

112 of 234 images (39 Identities (19 females) x 6 Expressions:

113 'happy'/'sad'/'fearful'/'angry'/'surprised'/'disgusted') were presented in random order. On each trial one

114 image was displayed on a black background with all the adjectives (in Persian) displayed alongside on the

115 right. Participants selected the best-fitting label by mouse, with no time limit.

116 2.3. Emotional dot-probe task

117 A subset of RaFD images (27 models; 12 female; fearful and neutral expressions) were used. Faces

118 were grayscale-transformed, equalized for intensity and contrast, and cropped to eliminate hair and other

119 features falling outside the oval borders (6° main diagonal).

120 Each trial (Fig. 2.A) started with a central black fixation cross (0.2° * 0.2°, 5 cd/m2; duration 1000ms)

121 on a uniform gray background (15 cd/m2). Subsequently, two face stimuli (same identity) were presented

122 at 7° eccentricity to the left and right of fixation. To probe the time-course of attentional effects, three cue

123 durations (100, 500, or 1000ms) were used. On disappearing, the cue was replaced immediately by the

124 target stimulus. The target was a circle or square (0.5° * 0.5°; dark-gray, 10 cd/m2) that appeared in the

125 left or right visual field (LVF, RVF) at 7° eccentricity with equal probability, and participants were

126 instructed to maintain central fixation and report the target's shape by pressing the designated keyboard

127 buttons. Accuracy and speed were equally emphasized.

128 We tested three conditions: 'congruent', 'incongruent', and 'neutral'. On neutral trials, the same face

129 with a neutral expression was displayed on both sides. In the other two conditions, one of the two faces

130 was fearful. In congruent trials (Fig. 2.A; left), the target appeared on the same side as the fearful face. In

131 incongruent trials (Fig. 2.A; middle) the target appeared on the opposite hemifield. In total each

132 participant completed 1440 trials over two testing sessions, each lasting approximately 40 minutes. Each

133 configuration (Cue duration * Trial type) occurred with equal probability in random order.

134 Based on previous studies (Mogg & Bradley, 1998), we reasoned that a positive congruency effect

135 [RTcongruent<RTincongruent] would indicate 'vigilance' to fear whereas the reverse effect would indicate fear

136 'avoidance'. Comparison with a baseline condition (without emotional cueing) is necessary to determine

137 the components of attentional bias (i.e., 'engagement' or 'disengagement') (Koster, Crombez,

138 Verschuere, et al., 2004). A positive congruency effect could be either due to 'facilitated engagement'

139 [RTcongruent<RTneutral] (Fig. 2.B; left) or 'difficulty in disengagement' [RTincongruent >RTneutral] (Fig. 2.B;

140 middle).

141 2.4. Statistical considerations

142 Analysis of single-case experiments requires special statistical methods (McIntosh & Brooks, 2011).

143 We employed the modified t test proposed by Crawford and Howell (1998) to test the significance of the

144 deficits in SF's fear sensitivity score and expression classification performance. This procedure is

145 particularly suited for comparing a single observation with the mean of a small control group (Crawford

146 & Garthwaite, 2006, 2012). The logic behind Crawford & Howell's method can be extended to analysis

147 of variance (ANOVA) procedure (Corballis, 2009b), and is valid for factorial analysis of scores measured

148 under several conditions of the same task (Corballis, 2009a; Crawford, Garthwaite, & Howell, 2009). See

149 Supplementary Material (§5) for further details and discussion of alternative statistical methods. We

150 applied ANOVA on mean reaction times of subjects to test for main effects and interactions between

151 conditions of the dot-probe experiment. For pairwise comparison between mean reaction times of SF in

152 each trial type (congruent, incongruent, neutral) we used the Crawford and Garthwaite's revised test for

153 difference (Crawford & Garthwaite, 2005). This method is a modified paired-sample t test suited for

154 comparing a patient's performance on parallel versions of a task with that of controls under two different

155 experimental conditions. Corresponding pairwise comparisons for control subjects were run using

156 conventional paired t tests. For confirmation, we reanalyzed SF's dot-probe data using trial-by-trial

157 reaction times (i.e., not averaged over conditions) and conventional statistical methods (Supplementary

158 Material, §6). IBM SPSS Statistics (Ver. 20.0) was used for data analysis. In SPSS software, the

159 Crawford and colleagues methods are applied by defining the single case as a group of N = 1 and no

160 further adjustment is required (Corballis, 2009a). In all tests ^-values<0.05 were considered significant

161 (with Bonferroni adjustment where appropriate).

162 3. Results

3.1. Fear sensitivity The FSSC-R questionnaire lists 80 specific situations or objects (e.g. "getting lost in a strange place",

165 "snakes", etc.). Participants described how much they fear each item ("none"/"some"/"a lot"; scored 1-3

166 respectively). SF scored 98, reporting "a lot" of fear for only three items (see Supplementary Material,

167 §1), while controls' scored significantly higher (M±5D=142±14.8; range: 119-168; t(9)=2.80;p=0.02)

168 (Fig. 3.A).

169 3.2. Facial expression classification

170 With the exception of fearful expressions, SF and controls were equally accurate (all p>0.05) in

171 identifying the relevant emotional label for the faces (Fig. 3.B). When a fearful face was presented, SF

172 chose the correct label in only 18% of trials, significantly lower than the average performance of controls

173 [72%; t(9)=3.85; p=0.004]. SF categorized fearful faces as 'surprised' in 69% of trials; whereas controls

174 had a broader distribution of errors (Fig. 3.C).

175 3.3. Emotional dot-probe task

176 Errors in reporting the shape of the target were rare. On average, controls made an error on 0.9% of

177 trials (SD=0.8). SF had a significantly higher error rate [3.1%; t(9)=2.53;p=0.032]. Prior to averaging

178 RTs, error trials and trials with outlier RTs were excluded. Outliers were defined separately for each

179 participant as RTs that deviated more than 1.5 inter-quartile ranges from the upper and lower quartiles.

180 These trials comprised 4.2% of SF's data and 2.5% of all collected data. We found no evidence for speed-

181 accuracy trade-off (see Supplementary Material, §4).

182 Mean RTs for each experimental condition (Supplementary Table 1) were entered into a 3-way

183 repeated measures ANOVA with Group (controls/SF) * Cue duration (100/500/1000ms) * Congruency

184 (congruent/incongruent) as factors. None of the main effects nor the 2-way interactions were significant.

185 However, a significant 3-way interaction [F(2, 18)=9.77; p=0.001] showed that the temporal pattern of

186 emotion-attention interaction differed between SF and controls. In follow-up tests, the Cue duration *

187 Congruency interaction was examined within SF and the control group separately and showed temporal

188 mediation of attentional effects in both SF [F(2, 18)=5.42; p=0.014] and controls [F(2, 18)=9.89;

189 p=0.001]. Note that in this analysis the RT from neutral trials are not included as they cannot be

190 differentiated as being congruent or incongruent. Attentional bias scores [RTcongruent-RTincongruent] for SF

191 and controls at each cue duration are presented in Figure 4.A. As mentioned earlier, comparison with

192 neutral trials' RT (i.e. baseline RT unaffected by attentional cueing) is necessary to determine which

193 component of spatial attention is affected (Koster, Crombez, Verschuere, et al., 2004). To reveal the

194 attentional behavior of SF and controls at each cue duration, we performed pairwise comparisons between

195 all the three trial types. Including the baseline condition tripled the number of planned tests. We used

196 Bonferroni adjustment to control the probability of false positives.

197 3.3.1. SF

198 With the shortest cue duration (100ms), SF showed a positive congruency effect [t(9)=3.31; p=0.027]

199 implying rapid vigilance for fear. This attentional bias disappeared with longer cue durations [500ms:

200 t(9)=0.78; p>0.l; 1000ms t(9)=2.06; p>0.1]. Pairwise comparison with baseline confirmed that at cue

201 durations of 100ms, SF showed facilitated engagement to fear location (RTcongruent<RTneutral [t(9)=2.96;

202 p=0.048]; no significant difference between RTincongruent and RTneutral [t(9)=0]) (Fig. 4.B). When cue

203 duration was 500ms, there was no bias but compared to the neutral condition, SF responded more slowly

204 in the emotional trials with significantly longer RTs in both congruent [t(9)=4.51; p=0.004] and

205 incongruent [t(9)=3.16; p=0.035] trials (Fig. 4.C). With the longest cue duration (1000ms), the

206 congruency effect was not statistically significant. Comparison with the neutral condition showed a

207 significant delay in responding to congruent trials [t(9)=2.96; p=0.048] but not incongruent trials

208 [t(9)=0.11] (Fig. 4.D).

209 3.3.2. Controls

210 With the shortest cue duration (100ms), controls showed a marginal effect of fear avoidance

211 [t(9)=2.87; p=0.056]. Longer cue durations resulted in significant attentional bias towards fear at both

212 500ms [t(9)=3.20; p=0.032] and 1000ms [t(9)=3.00; p=0.045] conditions. Comparison with baseline

213 revealed a trend for longer RTs in congruent trials in the 100ms condition [t(9)=2.79; p=0.064] (Fig. 4.E).

214 At cue durations of 500ms there was no significant difference between either congruent or incongruent

215 conditions and the baseline (Fig. 4.F). At cue durations of 1000ms the mean RT in incongruent trials was

216 significantly longer than neutral baseline [t(9)=3.77; p=0.013] suggesting that controls had difficulty in

217 disengaging fear location (Fig. 4.G).

218 4. Discussion

219 We investigated SF, a 14-year-old female with bilateral amygdala lesions due to UWD, and ten

220 matched controls. Psychiatric evaluation of SF revealed no pathological diagnosis. The fear survey

221 revealed her significantly lower fear sensitivity. These findings are consistent with prior reports from an

222 adult UWD patient (Feinstein, Adolphs, Damasio, & Tranel, 2011; Tranel, Gullickson, Koch, & Adolphs,

223 2006). Moreover we found that SF is specifically impaired in classifying the fearful facial expressions, a

224 frequent finding after the damage of amygdala either due to UWD (Adolphs, Tranel, Damasio, &

225 Damasio, 1994; Becker et al., 2012; Siebert, Markowitsch, & Bartel, 2003) or other less selective

226 pathologies (Schmolck & Squire, 2001; Sprengelmeyer et al., 1999).

227 Our main aim was to investigate the causal contribution of amygdala to the orienting of spatial

228 attention by fearful faces. We measured attentional bias using a dot-probe task with congruent and

229 incongruent cues and used various cue durations to investigate the temporal dynamics of attentional

230 biases. To discriminate between engagement and disengagement components of attention, we included

231 trials with neutral/neutral face pairs to measure baseline RTs. The results revealed that SF and controls

232 demonstrated opposite patterns of attentional biases in the early and late time-points after attentional cue

233 onset (Fig. 4.A). SF showed attentional bias towards fear at the shortest tested cue duration of 100ms. In

234 controls, the attentional bias towards fearful faces was observed in the middle and longer time windows

235 (5 00-1000ms post-cue). In contrast, SF showed no bias at the moderate cue durations, and only a weak

236 bias away from the fearful cue location at 1000ms. These findings suggest that SF's attention was rapidly

237 engaged to the fearful face but shortly afterwards her attention disengaged from the fear location (by a

238 timescale of <500ms post-cue) and proceeded to avoid the previously attended location possibly via a

239 mechanism similar to 'inhibition of return ' (Klein, 2000). Healthy subjects, on the other hand, showed

240 difficulty in disengaging attention from the location of fearful faces (Fig. 4.G). Our results reveal for the

241 first time the separable effects of amygdala damage on engagement and disengagement components of

242 spatial attention.

243 We found that the attentional bias in normal subjects was due to difficulty in disengaging attention

244 from the location of fear. SF showed an early bias towards fear due to facilitated engagement of attention,

245 but unlike the control group did not show disengagement cost at any of three measured time-points. This

246 is a peculiar finding because abundant dot-probe data demonstrate that unlike disengagement effects, that

247 might occur independently, facilitated engagement to emotion does not occur alone and is almost always

248 followed by difficulty in disengagement (Cisler & Koster, 2010). Our results thus imply that amygdala

249 damage abolishes the difficulty in disengaging from fear location at moderate to late time points,

250 suggesting that amygdala function is necessary for the disengagement costs to occur. Electrophysiological

251 and neuroimaging studies have begun to fractionate the neural underpinnings of the facilitated capture of

252 spatial attentional by fearful faces and the attentional disengagement costs imposed by such stimuli, and

253 are consistent with the suggestion that these effects have dissociable neural correlates (Pourtois et al.,

254 2005; Pourtois, Schwartz, Seghier, Lazeyras, & Vuilleumier, 2006). Future studies, could test whether

255 these neural mechanisms are causally dependent upon amygdala projections. Our current results imply

256 that amygdala actively increases the attentional dwell time on biologically significant signals.

257 Strikingly, we found rapid engagement of attention by fear in SF at the shortest cue duration. This

258 attentional bias suggests that despite bilateral amygdala damage and impairment of fear recognition,

259 fearful faces could nonetheless rapidly orient SF's spatial attention. Attentional orienting by such short

260 cue durations suggests that a reflexive, bottom-up mechanism is still functional in SF. This is consistent

261 with previous reports that the amygdala is not essential for rapidly detecting and attending to emotional

262 stimuli (Bach et al., 2011; Piech et al., 2010, 2011; Tsuchiya et al., 2009). But assuming no role for the

263 amygdala in orienting attention to emotion is problematic for interpreting multiple studies that showed

264 that projections from the amygdala modulated perceptual and attentional responses to fear-related stimuli

265 (Benuzzi et al., 2004; Rotshtein et al., 2010; Vuilleumier et al., 2004). Damage to amygdala abolishes

266 fear-induced enhancement of early visual responses (Rotshtein et al., 2010) and these early enhancements

267 appear functionally relevant to the attentional bias towards fear in the dot-probe paradigm (Pourtois,

268 Grandjean, Sander, & Vuilleumier, 2004). So what is the function of amygdala-mediated enhancement of

269 visual responses, if amygdala is not necessary for initial attention to fear?

270 Current theories propose that the function of amygdala is not specific to emotional processing, instead

271 playing a role in optimizing the allocation of perceptual resources to stimuli based on biological value and

272 goal relevance (Pessoa & Adolphs, 2010; Sander, Grafman, & Zalla, 2003). From this perspective it is

273 reasonable to think that amygdala might act to either facilitate or prevent orienting towards threat signals,

274 by weighing up the cost of ignoring potential danger against the benefit of goal-directed tasks (Pessoa,

275 2009). Indeed we found that compared to SF, the shift of attention towards fear arose later in healthy

276 controls. A brief task-irrelevant fearful face is a relatively weak signal of environmental danger—and is

277 safe to ignore, as controls did in the 100ms condition of our experiment. However, as the fearful face

278 persists its biological significance increases; at longer cue durations it is sensible to interrupt the task and

279 attend to the fearful face location—and engage with it until the potential source of threat is resolved. The

280 delay shown by healthy control participants in orienting to fear fits this ecological perspective on

281 amygdala function (Pessoa, 2009) and suggests that amygdala can actively act to suppress the fear bias

282 when threat is weak and irrelevant. This claim is supported by at least one other study of several UWD

283 patients which provided causal evidence that the basolateral amygdala nucleus is necessary to inhibit the

284 reflexive distraction of attention by task-irrelevant threat signals (Terburg et al., 2012). Without a

285 functional amygdala, SF showed reflexive attention to brief signals of fear and avoided the long-lasting

286 signals of potential threat. These are both harmful strategies and suggest that she was impaired in

287 adjusting attentional selection based on the biological significance of sensory events. The current set of

288 findings corroborate the notion that amygdala is crucial for top-down guidance of spatial attention to

289 biologically relevant and not necessarily emotional features of the visual scene (Jacobs, Renken, Aleman,

290 & Cornelissen, 2012; Pourtois et al., 2013). Remarkably, the failure in top-down guidance of attention

291 seems to be the basis of impaired recognition of fearful faces, which is the hallmark deficit of amygdala-

292 damaged patients. Studies on SM, the single-most studied UWD case (2008; 2005) suggest that

293 amygdala-damaged patients are not impaired in perception of fear per se, but fail to properly attend to

294 parts of face images that are relevant for correct expression recognition (Kennedy & Adolphs, 2011).

295 Intriguingly, SM's fear recognition deficit was corrected after an explicit instruction to attend to the eye

296 region of faces (Adolphs et al., 2005). Our patient mostly labelled 'fearful' faces as 'surprised' (see Fig

297 3.C). Compared to other expressions, there is more overlap between the facial features that relay fear and

298 surprise emotions (Smith, Cottrell, Gosselin, & Schyns, 2005) and discriminating the two relies on active

299 attentional selection (Schyns, Petro, & Smith, 2009). Therefore, SF's deficit in the facial expression

300 classification task might also be consistent with a role for amygdala in top-down attentional guidance.

301 Here we discussed findings from a single case study. For this reason, caution should be exercised in

302 interpreting the results for amygdala's attentional function based on this study alone. Further studies on

303 patients with bilateral amygdala damage are needed to confirm current results. Several points should be

304 noted in conducting future studies. First, the amygdala is a heterogeneous structure and animal studies

305 have found disparate behavioral outcomes after lesions of specific subnuclei (Swanson & Petrovich,

306 1998). Precise characterization of location and extent of patient's lesions, might help reconcile the reports

307 of diminished (Anderson & Phelps, 2001), preserved (Bach et al., 2011), and even increased attention to

308 fear after amygdala damage (Terburg et al., 2012). Second, here we only used task-irrelevant fearful faces

309 to cue attention. The consequences of amygdala damage on attentional orientation by task-relevant and

310 more potent danger signals remain to be investigated. Third, we relied on changes in RT to study

311 attentional effects. However, threat-signals affect both the latency (Pessoa, Padmala, Kenzer, & Bauer,

312 2012) and accuracy (Phelps, Ling, & Carrasco, 2006) of perceptual responses—occasionally in opposing

313 directions (Bocanegra, 2014). The separable roles of amygdala in mechanisms underlying speed-accuracy

314 trade-offs is an important, yet unstudied topic. Future research should focus on explicit characterization of

315 the time-course, attentional components, and neural pathways that comprise interactions between

316 amygdala and attentional effects (Cisler & Koster, 2010). This seems a promising approach for

317 unravelling amygdala's functions, and it's role in pathophysiology of anxiety disorders (Birn et al., 2014;

318 Milham et al., 2005). Abnormal attentional bias towards threat robustly relates to elevated trait anxiety

319 (Bar-Haim, Lamy, Pergamin, Bakermans-Kranenburg, & van IJzendoorn, 2007; Hakamata et al., 2010),

320 and fUture theories must address such relationships.

321 5. Conclusion

322 We showed that an adolescent patient with bilateral amygdala damage rapidly attended fearful faces,

323 but disengaged from them prematurely. To our knowledge, this is the first demonstration of the separable

324 effects of amygdala damage on engagement and disengagement components of spatial attention. Our

325 findings show that attentional behavior is shaped by multiple influences from amygdala, occurring at

326 distinct time points; and suggest that the amygdala has a modulatory role in threat-related attentional bias.

327 It seems that the amygdala is not essential for rapid attention to emotion. Instead, the amygdala probably

328 has a crucial role in assessing the biological relevance of sensory events, and is essential for efficient

329 allocation of perceptual resources.

330 Acknowledgements

331 The authors would like to thank SF and her family for their cooperation and the Tazkieh High School

332 for assistance in recruiting the control subjects. BB is supported by the European Research Council

333 (Grant No. 309865 NEUROCODEC). JSW is supported by the Wellcome Trust (Grant No. 095939) and

334 the Wellcome Trust Centre for Neuroimaging is supported by core funding from the Wellcome

335 Trust (Grant No. 091593). This work was supported by Tehran University of Medical Sciences (Grant

336 No. 91-01-3017196 to AT).

337 Financial Disclosure

338 The authors report no biomedical financial interests or potential conflicts of interest.

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564 Figure Legends

565 Figure 1. T1, T2, and FLAIR sequence MRI of SF. Images demonstrate bilateral amygdala lesions

566 (arrowheads) as a result of symmetrical calcifications due to Urbach-Wiethe disease. Each column

567 presents corresponding axial sections; from left to right at 24, 18, and 12 millimiters below the anterior

568 commissure. Images are in radiological convention.

569 Figure 2. Stimuli sequence, experimental conditions, and alternative results of the dot-probe task.

570 (A) Each trial started with a fixation cross. Each cue display consisted of a pair of face image of the same

571 identity. On neutral trials (right), the same face with a neutral expression was displayed on both sides. In

572 the other two conditions, one of the two faces was fearful. In congruent trials (left), the target appeared on

573 the same side as the fearful face. In incongruent trials (middle) the target appeared on the opposite

574 hemifield. Three cue durations (100, 500, and 1000ms) occurred with equal probability. Stimuli are not

575 drawn to scale. (B) Schematics of typical behavioral results obtained in dot-probe tasks. Significant

576 difference between reaction times (RT) in congruent and incongruent trials indicates an attentional bias

577 towards (left and middle panels) or away (right panel) from fear. A positive congruency effect could be

578 due to either 'facilitated engagement' (left) or 'difficulty in disengagement' (right). Comparison with

579 baseline (RT in neutral trials; horizontal black lines) is necessary to determine the affected components of

580 attentional bias.

581 Figure 3. Deficits in experiential emotion processing with developmental amygdala damage. (A)

582 Participants' scores from the Fear Survey Schedule for Children-Revised (FSSC-R). SF had a

583 significantly lower score, suggesting that she had lower everyday experience of fear. (B) Performance

584 accuracy in the facial expression classification task. SF was specifically impaired in classifying the fearful

585 facial expression. (C) Distribution of labels assigned to fearful faces. SF assigned the 'surprised' label to

586 69% of the fearful faces.

587 Figure 4. Results of the dot-probe task. Panel (A) shows the attentional bias scores of SF and controls

588 at each cue exposure duration. Bias score is calculated by subtracting reaction times on congruent trials

589 from reaction times on incongruent trials. Positive attentional bias scores indicate attention towards the

590 fearful face. Negative scores indicate avoidance of fear location. Panels (B-G) show mean reaction time

591 of SF and controls on congruent, incongruent, and neutral trials at each cue exposure duration. SF showed

592 attentional bias towards fearful faces mediated by facilitated engagement effect at 100ms (B); generally

593 slower reaction times in trials including a fearful face, but no significant attentional bias at 500ms (C);

594 and bias to avoid the location of fearful faces, probably due to inhibition of return at the exposure

595 duration of 1000ms (D). Controls showed a trend to avoid fearful faces at 100ms (E); significant

596 attentional bias was observed afterwards at 500ms (F); and at 1000ms mediated by difficulty to disengage

597 from the location of fearful faces (G). Horizontal black lines indicate the mean reaction time at neutral

598 trials. Dotted lines represent significant difference with baseline. Error bars show ±standard error of

599 mean, representing within-subject variance in SF (uncapped bars) and between-subject variance in

600 controls (capped bars). * p <0.05, ** p <0.01

Z = -24

Z = -18

Z = -12


till response or 2000 ms

100, 500 or 1000 ms


1000 ms




Positive congruency effect (Vigilance)

Facilitated engagement Difficulty in disengagement

[RTcongruent < RTincongruent]

Incongruent Congruent

[RTincongruent > RTneutral.

Incongruent Congruent

Negative congruency effect (Avoidance)

[RTcongruent > RTincongruent]

[RTincongruent < RTneutral.

Incongruent Congruent

co o Vi co m _co

□ SF ♦ Controls

100%-80%" 60%" 40%-20% 0%

angry disgusted fearful happy Facial expression

<D 80%-

co 60%"

40% 20% 0%

angry disgusted fearful happy

sad surprised

sad surprised

Label chosen in response to fearful faces

Cue duration

^_) 690-

s—( 670-

c 650-


o co 630-

C co 610-


100 ms

500 ms

1000 ms

'(B) : '(C) 1 ** '(D)

(E ) (F ) '(G) xr<4

Trial type

Incongruent Congruent Incongruent Congruent Incongruent Congruent